Crystallization from solution is an important separation and purification process in the chemical process industries. It is the primary method for the production of a wide variety of materials ranging from inorganic compounds, such as calcium carbonate and soda ash, to high added value materials, such as pharmaceuticals and specialty chemicals. In addition to product purity, crystallization must also produce particles of the desired size and shape, as well as particles of the desired polymorph.
Chemicals have the ability to crystallize into more than one distinct crystal structure. This ability is called polymorphism (or, if the species is an element, allotropism). Different polymorphs of the same material can display significant changes in their properties, as well as in their structures. These properties include density, shape, vapor pressure, solubility, dissolution rate, bioavailability, and electrical conductivity. Polymorphism is quite common among the elements and also for inorganic and organic chemicals. It is especially prevalent in organic molecular crystals, which often possess multiple polymorphs. The incidence of polymorphism in organic molecular crystals bears great significance to the pharmaceutical, dye, agricultural; chemical, and explosives industries.
Under a given set of conditions, one polymorph exists as the thermodynamically stable form. This is not to say, however, that the other polymorphs cannot exist or form in these conditions. It means only that one polymorph is stable while the other polymorphs can transform to the stable form. In pharmaceutical product development, the most stable polymorph has, generally, been selected for employment in the final dosage product. Yet in recent years, metastable forms have often been utilized due to their enhanced dissolution and/or bioavailability. In these cases, an understanding of the stability of these metastable forms under processing and storage conditions has proven crucial for the safety and efficacy of the drug. Usually regulatory authorities regulate both the drug substance and the polymorph for all crystalline pharmaceuticals and require extensive studies of polymorph stability.
Crystallization from solution begins with the nucleation of crystals followed by the growth of these nuclei to finite size. Nucleation and growth follow separate kinetic regimes with nucleation normally occurring at high driving forces (oversaturation) and growth occurring at all levels of oversaturations. The growth rate is usually faster at increasing oversaturation levels. Beyond a critical oversaturation there will be spontaneous nucleation of new nuclei. If one wants to prevent such extra nucleation, one needs to keep the oversaturation below said critical oversaturation value during growth. The critical oversaturation needs to be determined for each precipitating compound and each precipitating condition(such as kind of solvent, temperature, etc.). A major problem with usual crystallization methods is that with substances that form organic molecular crystals it can be difficult to obtain high oversaturations. High oversaturation meaning a value (S) higher than for example 5; (S being defined as the actual concentration of a substance divide by the concentration when the substance in the particular solvent is just saturated). Another problem is that these methods can produce an undesired polymorph because of the inadequate levels of oversaturation used or the inhomogeneous distribution of the oversaturation throughout the reaction vessel
In the field of photography methods and apparatus are known for the preparation of silver halide emulsions. A particular method for the preparation of photographic silver halide emulsions makes use of a nucleation chamber into which an aqueous solution of halide and an aqueous solution of silver salt are separately and simultaneously added. The nucleation chamber is positioned in a larger growth or ripening chamber in to which the silver halide nuclei are discharged to grow further into the desired silver halide crystals. Suitable apparatus for carrying out such a method for producing silver halide crystals are described in U.S. Pat. No. 4,289,733, EP 523842, EP 708362, EP 1357423, EP 0 709 723, U.S. Pat. No. 2003/0224308, U.S. Pat. No. 6,050,720 and U.S. Pat. NO. 5,202,226. In the field of silver halide emulsions for photography, polymorphism of silver halide crystals has never been an issue. The methods and apparatus cited above always dealt with the problem of obtaining silver halide emulsions with narrow crystal or silver halide grain size distributions.
U.S. Pat. No. 6,050,720 concerns apparatus for the preparation of photographic silver halide emulsions. In passing it is noted that the apparatus can be used for agitating and mixing various solutions.
EP 523842 discloses a method of producing gold and silver chalcogenides, hence gold and silver salts of sulfur, selenium, and tellurium. These salts are sparingly water-soluble. No other crystals than those that are sparingly soluble in water and in fact no other crystals than of the same type as silver halide crystals are disclosed and contemplated.
EP 1357423 concerns a method and apparatus for forming silver halide emulsions. It is described that also semiconductor particles can be formed. In fact only particles of group II elements and group VI elements, hence of the same type as silver halide crystals, are suggested.